The objective of this research program is to define the molecular mechanisms that regulate the inflammatory process. One effector molecule that has been implicated as a regulator of inflammatory responses is transforming growth factor beta (TGF-beta). The TGF- beta1 (-/-) mouse provides a model to explore the in vivo regulatory role of TGF-beta1 in development and immune responses. These mice develop multifocal inflammatory lesions in vital organs and die within 3-4 weeks. Periductal lymphocytic infiltration in the salivary and lacrimal glands results in glandular atrophy and acini destruction and contributes to clinical manifestations of xerostomia and keratoconjunctivitis sicca. The inflammatory pathology and autoantibdy production are consistent with autoimmune etiology and resemble Sjogren's Syndrome. Increased cytokine expression in the TGF-beta1 (-/-) mice before evidence of an inflammatory lesion suggests that deficiency of the immunosuppressive activities of TGF- beta1 may directly influence cytokine expression and contribute to the initiation of the autoimune-like syndrome. Dysregulation of adhesion molecule expression is evident by 3-5 days of age and represents the first detectable event leading to inflammation in the TGF-beta1 (-/-) mice. Treatment with adhesion-blocking fibronectin peptides prevented leukocyte infiltration and tissue pathology and restored function of salivary and lacrimal glands of the TGF-beta1 (- /-) mice. The TGF-beta1 (-/-) mice provide an important model of autoimmune disease which can be utilized in the design of therapeutic interventions.